A Phase I Trial of Vandetanib (AZD6474) and Selumetinib (AZD6244) for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)

Sponsor
Cancer Research UK (Other)
Overall Status
Completed
CT.gov ID
NCT01586624
Collaborator
AstraZeneca (Industry)
61
4
8
101
15.3
0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether using two drugs together called vandetanib and selumetinib is effective in the treatment of cancer. The first part of this study will include patients with any solid tumour and the second part of this study will include only patients with non small cell lung cancer. The four main aims of this clinical study are to find out:

  • If the two drugs can be given safely to patients when given together.

  • The maximum dose that can be given safely to patients.

  • More about the potential side effects of the drugs and how they can be managed.

  • What happens to vandetanib and selumetinib inside the body.

Condition or Disease Intervention/Treatment Phase
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
  • Drug: Vandetanib, Selumetinib
Phase 1

Detailed Description

The purpose of this Phase I study is to establish a safety and toxicity profile of combining two study drugs; vandetanib, a VEGFR (Vascular Endothelial Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor) inhibitor, with selumetinib a MEK (Mitogen Activated Kinase) inhibitor.

This is the first time the drugs have been used together. These types of drugs have shown an effect in non small cell lung cancer (NSCLC).

The study is in two parts; the dose escalation phase and the expansion phase.

In the dose escalation phase, 42-50 patients will receive different doses of vandetanib and increasing doses of selumetinib to establish a safe dose to recommend for the next stage of the study. Patients with any solid tumour will be eligible.

In the expansion phase, up to 30 patients will receive the dose recommended in the previous phase. Only patients with NSCLC will be eligible for this part of the study.

The expansion phase will look at further evaluating the safety of the drug combination and the anti-tumour activity. Patients in this cohort will be requested to also consent to have additional imaging assessments and optional tumour biopsies.

Study treatment is administered orally; vandetanib tablets once daily and selumetinib capsules once daily (OD)/twice daily (BD). Cycle 1 is 42 days long. Subsequent cycles are 28 days in length. Patients will receive a total of 6 cycles of the combination treatment. If the patient has not progressed after six cycles, they may be treated for further cycles following approval from the sponsor.

Study Design

Study Type:
Interventional
Actual Enrollment :
61 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Cancer Research UK Phase I Dose Escalation Trial of Oral VEGFR and EGFR Inhibitor, Vandetanib in Combination With the Oral MEK Inhibitor, Selumetinib (VanSel-1) in Solid Tumours (Dose Escalation) and NSCLC (Expansion Cohort).
Actual Study Start Date :
Jan 10, 2012
Actual Primary Completion Date :
Jun 11, 2020
Actual Study Completion Date :
Jun 11, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose Escalation Phase Cohort 1 (Steady state dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 2 (Steady state dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 3 (Steady state dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 4 (Steady state dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 5a (Steady state dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 5b (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Dose Escalation Phase Cohort 6 (Steady state dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Experimental: Expansion Phase (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase.

Drug: Vandetanib, Selumetinib
Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Outcome Measures

Primary Outcome Measures

  1. Number of Serious Adverse Events, Non-serious Adverse Events and Treatment Emergent Adverse Events. [Safety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months).]

    Number of serious adverse events, non-serious adverse events and treatment emergent adverse events.

  2. Number of Dose Limiting Toxicities (DLTs) Within Each Cohort. [DLTs occurring in the first Cycle (up to Day 42).]

    Number of DLTs within each cohort.

Secondary Outcome Measures

  1. Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Vandetanib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Maximum observed plasma concentration of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.

  2. Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Maximum observed plasma concentration of selumetinib post treatment with the combination of vandetanib and selumetinib.

  3. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-24 Hours) of Vandetanib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-24 hours) of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.

  4. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-12 hours) of selumetinib post treatment with the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.

  5. Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of N-desmethyl Metabolite of Selumetinib. [0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.]

    Area under the plasma concentration time curve (0-12 hours) of N-desmethyl metabolite of selumetinib following the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.

  6. Expansion Cohort Only: Progression Free Survival (PFS) of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib. [10 and 18 weeks from date of first dose of vandetanib.]

    PFS by Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0). Per RECIST for target lesions and assessed by computerised tomography (CT), progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum while on trial, or the appearance of one or more new lesions.

  7. Expansion Cohort Only: One Year Survival of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib. [1 year from date of first dose of vandetanib.]

    Number of patients alive at one year.

  8. Expansion Cohort Only: Tumour Metabolism in Patients With NSCLC Using Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) Criteria. [Baseline, Day 12, Day 42.]

    Tumour metabolism using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) computerised tomography (CT) imaging pre and post treatment with vandetanib alone and following the combination of vandetanib and selumetinib. These were assessed and reported according to PERCIST criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. (Dose escalation cohorts) Histologically or cytologically proven solid tumour for which no conventional therapy exists or is declined by the patient

  2. (Expansion cohort only) Histologically or cytologically confirmed NSCLC patients only, for which no conventional therapy exists or is declined by the patient.

  • If only cytologically confirmed, baseline biopsy is mandatory for a patient to be eligible.

  • For NSCLC patients to be eligible for the expansion cohort they must have received:

  • One prior line of chemotherapy and/or

  • Previous platinum based chemotherapy and/or

  • At least one previous EGFR inhibitor

  1. (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.1 in final version of the protocol

  2. Life expectancy of at least 12 weeks

  3. World Health Organisation (WHO) performance status of 0-1

  4. Baseline LVEF > 50%

  5. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day -1) before the patient goes on study.

Laboratory Test Value required

Haemoglobin (Hb) ≥ 9.0 g/dL

Absolute neutrophil count ≥ 1.5 x 10^9/L

Platelet count ≥ 100 x 10^9 /L

Normal serum calcium (adjusted)* 2.15-2.55 mmol/L

Normal serum magnesium* 0.60-1.0 mmol/L

Normal serum potassium >4.0 mmol/L

Either: Serum bilirubin ≥1.5 x upper limit of normal (ULN) This does not apply to patients with Gilbert's disease.

Alanine amino-transferase (ALT) or aspartate amino-transferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 x ULN unless raised due to liver metastases in which case up to 5 x ULN is permissible

Either: Calculated creatinine clearance (using the Wright or C&G formula) > 50 mL/min

Or: Isotope clearance measurement** ≥ 50 mL/min (uncorrected)

INR or aPTT < 1.5 x ULN

*or normal range according to the local laboratory

** Isotope clearance result to be used to confirm eligibility if calculated C&G/Wright method results in GFR of = 50 mL/min.

*** Therapeutic INR values (2.0-3.0) are acceptable to confirm eligibility for patients who are taking concomitant warfarin.

  1. 18 years or over

  2. Ability to swallow and retain oral medications.

  3. Written (signed and dated) informed consent and be capable of co-operating with treatment, and follow-up

Exclusion Criteria:
  1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous 4 weeks (6 weeks for investigational medicinal products) before treatment.

  2. Patients who have been withdrawn from treatment with agents that target EGFR because of unacceptable toxicity (prior treatment with these agents is allowed) and those patients who have had EGFR dose reductions by 50% or more.

  3. Expansion cohort only: Prior treatment with any agent that targets MEK or VEGFR

  4. Any prior exposure to RAS or RAF inhibitors

  5. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 2 toxicities, which in the opinion of the Investigator and the Centre for Drug Development (CDD) should not exclude the patient.

  6. Symptomatic brain metastases (patients must be stable for >3 months post RT treatment) or spinal cord compression.

  7. Patients with interstitial lung disease.

  8. Pregnant or lactating women are excluded. Female patients with the ability to become pregnant who have a negative serum or urine pregnancy test before enrollment and agree to use two of the following three highly effective forms of combined contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.

  9. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

  10. Major surgery from which the patient has not yet recovered.

  11. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.

  12. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).

  13. Cardiac conditions as follows:

  • Clinically significant cardiovascular event within 3 months prior to entry to include:

  • Myocardial infarction

  • Angina requiring use of nitrates more than once weekly

  • Superior vena cava syndrome

  • Class II/III/IV cardiac disease (New York Heart Association [NYHA])

  • Presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.

  • History of arrhythmia which is symptomatic or requires treatment (CTCAE V4.02), symptomatic or uncontrolled atrial fibrillation despite treatment or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.

  • Uncontrolled hypertension (BP > 160/100 despite optimal therapy)

  • Prior or current cardiomyopathy

  • Atrial fibrillation with heart rate > 100 bpm

  • QTcB > or equal to 450 msec on screening ECG (Note: If a patient has a QTcB interval > or equal to 450 msec on screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]. The average QTcB from the three screening ECGs must be < 450 msec in order for the subject to be eligible for the study.)

  • History of congenital long QT syndrome

  • History of Torsade de Pointes (or any concurrent medication with a known risk of inducing Torsades de Pointes.)

  1. Concomitant medications that are potent inducers of CYP3A4 function i.e. rifampicin, rifabutin, phenytoin, carbamazepine, Phenobarbital and St John"s Wort.

  2. Any other condition which in the Investigator"s opinion would not make the patient a good candidate for the clinical trial (e.g. evidence of severe or uncontrolled systemic disease or concurrent condition or that may affect ability to absorb oral agents).

  3. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years or more and are deemed at negligible risk for recurrence, are eligible for the trial.

  4. If a participant plans to participate in another interventional clinical study, whilst taking part in this Phase I study. Participation in an observational study would be acceptable.

  5. Ophthalmological conditions as follows:

  6. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion.

  7. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Churchill Hospital Headington Oxford United Kingdom
2 Addenbrooke's Hospital Cambridge United Kingdom
3 The Christie Hospital Manchester United Kingdom
4 Freeman Hospital Newcastle United Kingdom

Sponsors and Collaborators

  • Cancer Research UK
  • AstraZeneca

Investigators

  • Principal Investigator: Denis Talbot, Prof, Oxford University Hospitals NHS Trust

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01586624
Other Study ID Numbers:
  • CRUKD/11/001
  • 2011-000627-33
First Posted:
Apr 27, 2012
Last Update Posted:
Oct 7, 2021
Last Verified:
Sep 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Cancer Research UK
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Trial participants were enrolled at three trial sites between 10 January 2012 and 19 September 2017.
Pre-assignment Detail
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Period Title: Overall Study
STARTED 6 6 6 7 9 8 8 11
COMPLETED 2 2 1 0 1 0 0 1
NOT COMPLETED 4 4 5 7 8 8 8 10

Baseline Characteristics

Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib ) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib ) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Total
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Total of all reporting groups
Overall Participants 6 6 6 7 9 8 8 11 61
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Between 18 and 65 years
0
0%
5
83.3%
3
50%
5
71.4%
3
33.3%
3
37.5%
4
50%
6
54.5%
29
47.5%
>=65 years
6
100%
1
16.7%
3
50%
2
28.6%
6
66.7%
5
62.5%
4
50%
5
45.5%
32
52.5%
Sex: Female, Male (Count of Participants)
Female
3
50%
2
33.3%
4
66.7%
4
57.1%
2
22.2%
6
75%
4
50%
6
54.5%
31
50.8%
Male
3
50%
4
66.7%
2
33.3%
3
42.9%
7
77.8%
2
25%
4
50%
5
45.5%
30
49.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]
0
0%
Region of Enrollment (participants) [Number]
United Kingdom
6
100%
6
100%
6
100%
7
100%
9
100%
8
100%
8
100%
11
100%
61
100%

Outcome Measures

1. Primary Outcome
Title Number of Serious Adverse Events, Non-serious Adverse Events and Treatment Emergent Adverse Events.
Description Number of serious adverse events, non-serious adverse events and treatment emergent adverse events.
Time Frame Safety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months).

Outcome Measure Data

Analysis Population Description
All patients who met the eligibility criteria and received at least one dose of the combination treatment (vandetanib and selumetinib) were evaluable for safety assessment (N=57).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 7 6 11
Total SAEs
10
11
13
5
28
10
14
14
Total NSAEs
99
90
70
94
161
98
114
130
Total treatment emergent AEs
107
99
79
93
165
102
126
135
2. Primary Outcome
Title Number of Dose Limiting Toxicities (DLTs) Within Each Cohort.
Description Number of DLTs within each cohort.
Time Frame DLTs occurring in the first Cycle (up to Day 42).

Outcome Measure Data

Analysis Population Description
All patients who met the eligibility criteria and received at least one dose of the combination treatment (vandetanib and selumetinib) were evaluable for safety assessment (N=57).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 7 6 11
Number [DLTs]
1
0
1
1
2
1
1
2
3. Secondary Outcome
Title Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Vandetanib.
Description Maximum observed plasma concentration of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.
Time Frame 0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 8 6
Day 4
585
561
582
790
484.5
702.5
702
Day 15
503.5
436
414.5
476
401.5
701
906
Day 29
556
399
538
503
335.5
988
902
4. Secondary Outcome
Title Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Selumetinib.
Description Maximum observed plasma concentration of selumetinib post treatment with the combination of vandetanib and selumetinib.
Time Frame 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 8 6
Day 15
324.5
605
1280
1890
2005
501
814
Day 29
430
569
1220
1740
1440
587
593
5. Secondary Outcome
Title Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-24 Hours) of Vandetanib.
Description Area under the plasma concentration time curve (0-24 hours) of vandetanib post treatment with vandetanib alone and following the combination of vandetanib and selumetinib.
Time Frame 0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 8 6
Day 4
12032
11629.5
11189
16603
10286.5
14395
14830.5
Day 15
9253.5
8822.5
7958.5
9946
8814.5
15442
18864
Day 29
12555
8355
11246
10058
7261.5
18573
15923
6. Secondary Outcome
Title Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of Selumetinib.
Description Area under the plasma concentration time curve (0-12 hours) of selumetinib post treatment with the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.
Time Frame 0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 8 6
Day 15
1251.5
2050
4072.5
6138
6921
1698
2770
Day 29
1913
2550
4762
6998
6429
3049
2477
7. Secondary Outcome
Title Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of N-desmethyl Metabolite of Selumetinib.
Description Area under the plasma concentration time curve (0-12 hours) of N-desmethyl metabolite of selumetinib following the combination of vandetanib and selumetinib. This was extrapolated from the sampling data up to 10 hours to allow comparison with literature data.
Time Frame 0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

Outcome Measure Data

Analysis Population Description
All patients in the dose escalation cohorts (Cohorts 1 to 6) who received at least one dose of IMP (N=47 with available PK data).
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 (Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 6 6 6 7 8 8 6
Day 15
78.5
141
255
349
493
182
236
Day 29
89
163
230
390
377
293
205
8. Secondary Outcome
Title Expansion Cohort Only: Progression Free Survival (PFS) of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib.
Description PFS by Response Evaluation Criteria in Solid Tumours Criteria (RECIST v1.0). Per RECIST for target lesions and assessed by computerised tomography (CT), progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum while on trial, or the appearance of one or more new lesions.
Time Frame 10 and 18 weeks from date of first dose of vandetanib.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group Title Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 9
Progression free at 10 weeks
3
50%
Progression free at 18 weeks
2
33.3%
9. Secondary Outcome
Title Expansion Cohort Only: One Year Survival of Patients With NSCLC After Treatment With the Combination of Vandetanib and Selumetinib.
Description Number of patients alive at one year.
Time Frame 1 year from date of first dose of vandetanib.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group Title Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 9
Number [participants]
2
33.3%
10. Secondary Outcome
Title Expansion Cohort Only: Tumour Metabolism in Patients With NSCLC Using Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) Criteria.
Description Tumour metabolism using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) computerised tomography (CT) imaging pre and post treatment with vandetanib alone and following the combination of vandetanib and selumetinib. These were assessed and reported according to PERCIST criteria.
Time Frame Baseline, Day 12, Day 42.

Outcome Measure Data

Analysis Population Description
All patients in the expansion cohort receiving at least one cycle* of the vandetanib and selumetinib combination with a baseline assessment of disease (N=9). *To be evaluable for response, a patient must have received a minimum of 21 of the 28 daily doses of the combination treatment in Cycle 1.
Arm/Group Title Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
Measure Participants 9
Day 12 Complete Metabolic Response
0
0%
Day 12 Partial Metabolic Response
0
0%
Day 12 Stable Metabolic Disease
8
133.3%
Day 12 Progressive Metabolic Disease
1
16.7%
Day 42 Complete Metabolic Response
0
0%
Day 42 Partial Metabolic Response
2
33.3%
Day 42 Stable Metabolic Disease
3
50%
Day 42 Progressive Metabolic Disease
2
33.3%
Day 42 Not assessed
2
33.3%

Adverse Events

Time Frame Safety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months). Overall Mortality was collected during the Safety data assessment period for the dose Escalation Cohorts and up to one year after Cycle 1 Day 1 for the Expansion Cohort.
Adverse Event Reporting Description Per protocol, where deaths due to disease progression were reported as AEs, these weren't considered to be SAEs unless related to the IMP. These events were coded by the Sponsor as "Death NOS" in the clinical database but have been entered as disease progression at the request of ClinicalTrials.gov. For patients recruited to the expansion cohort, deaths due to disease progression in the survival follow-up period were not reported as AEs but have been included in the All-cause mortality numbers.
Arm/Group Title Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Arm/Group Description Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 75 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 100 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 125 mg of selumetinib OD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Dose escalation to determine the recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 2) followed by vandetanib steady state dose of 300 mg OD (Days 3 to 14) followed by vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 300 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment. Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase. Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 200 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 200 mg OD + 50 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.
All Cause Mortality
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/6 (0%) 1/6 (16.7%) 2/6 (33.3%) 0/7 (0%) 1/8 (12.5%) 0/7 (0%) 1/6 (16.7%) 7/11 (63.6%)
Serious Adverse Events
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/6 (66.7%) 4/6 (66.7%) 6/6 (100%) 2/7 (28.6%) 7/8 (87.5%) 5/7 (71.4%) 6/6 (100%) 8/11 (72.7%)
Cardiac disorders
Cardiac disorders - Other, specify 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Paroxysmal atrial tachycardia 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Sinus bradycardia 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Pericardial effusion 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Eye disorders
Eye disorders - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 2 1/11 (9.1%) 1
Retinal detachment 0/6 (0%) 0/6 (0%) 2/6 (33.3%) 2 0/7 (0%) 2 3/8 (37.5%) 4 1/7 (14.3%) 1 3/6 (50%) 3 1/11 (9.1%) 1
Retinal vascular disorder 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Retinopathy 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Gastrointestinal disorders
Abdominal pain 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 3 0/7 (0%) 3 0/6 (0%) 3 0/11 (0%) 3
Diarrhea 2/6 (33.3%) 2 2/6 (33.3%) 2 1/6 (16.7%) 1 0/7 (0%) 1 2/8 (25%) 8 0/7 (0%) 8 1/6 (16.7%) 2 3/11 (27.3%) 3
Dysphagia 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Gastrointestinal disorders - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Nausea 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Obstruction gastric 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Vomiting 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 4 0/7 (0%) 4 0/6 (0%) 4 1/11 (9.1%) 1
General disorders
Disease Progression 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Fever 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Infections and infestations
Biliary tract infection 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Infections and infestations - Other, specify 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Lung infection 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Urinary tract infection 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Metabolism and nutrition disorders
Dehydration 1/6 (16.7%) 2 0/6 (0%) 2 0/6 (0%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Hypercalcemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Hyponatremia 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Pain in extremity 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Nervous system disorders
Stroke 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Ischemia cerebrovascular 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Presyncope 0/6 (0%) 0/6 (0%) 2/6 (33.3%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Renal and urinary disorders
Acute kidney injury 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 2/11 (18.2%) 2
Urine discoloration 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Urinary retention 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Respiratory, thoracic and mediastinal disorders
Bronchopleural fistula 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Dyspnea 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Hypoxia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Laryngeal hemorrhage 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Respiratory, thoracic and mediastinal disorders - Other, specify 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Skin and subcutaneous tissue disorders
Erythroderma 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Rash acneiform 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 3/6 (50%) 3 0/11 (0%) 3
Rash maculo-papular 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 2 0/7 (0%) 2 0/6 (0%) 2 3/11 (27.3%) 3
Vascular disorders
Thromboembolic event 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Other (Not Including Serious) Adverse Events
Dose Escalation Phase Cohort 1 (Steady State Dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib) Dose Escalation Phase Cohort 2 ( Steady State Dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 3 (Steady State Dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib) Dose Escalation Phase Cohort 4 (Steady State Dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib) Dose Escalation Phase Cohort 5a (Steady State Dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib) Dose Escalation Phase Cohort 5b (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib) Dose Escalation Phase Cohort 6 (Steady State Dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib) Expansion Phase (Steady State Dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 6/6 (100%) 6/6 (100%) 6/6 (100%) 7/7 (100%) 8/8 (100%) 7/7 (100%) 6/6 (100%) 11/11 (100%)
Blood and lymphatic system disorders
Anaemia 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 1/7 (14.3%) 1 0/8 (0%) 1 1/7 (14.3%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Cardiac disorders
Chest pain - cardiac 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Cardiac disorders - Other, specify 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Palpitations 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Atrial fibrillation 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Sinus bradycardia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Sinus tachycardia 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 2/8 (25%) 2 0/7 (0%) 2 0/6 (0%) 2 1/11 (9.1%) 1
Ear and labyrinth disorders
Hearing impaired 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Ear and labyrinth disorders - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Eye disorders
Blurred vision 2/6 (33.3%) 2 0/6 (0%) 2 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 1/6 (16.7%) 2 1/11 (9.1%) 1
Eye disorders - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 2/7 (28.6%) 2 0/8 (0%) 2 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Eyelid function disorder 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Flashing lights 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Floaters 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Glaucoma 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Gastrointestinal disorders
Abdominal distension 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Abdominal pain 3/6 (50%) 3 0/6 (0%) 3 0/6 (0%) 3 1/7 (14.3%) 3 3/8 (37.5%) 6 3/7 (42.9%) 3 2/6 (33.3%) 2 0/11 (0%) 2
Bloating 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Colitis 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Constipation 2/6 (33.3%) 3 3/6 (50%) 3 1/6 (16.7%) 1 2/7 (28.6%) 3 2/8 (25%) 3 2/7 (28.6%) 2 0/6 (0%) 2 1/11 (9.1%) 1
Diarrhea 5/6 (83.3%) 7 5/6 (83.3%) 12 5/6 (83.3%) 6 4/7 (57.1%) 6 5/8 (62.5%) 17 7/7 (100%) 17 5/6 (83.3%) 14 8/11 (72.7%) 16
Dry mouth 1/6 (16.7%) 1 1/6 (16.7%) 2 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Dyspepsia 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Esophageal hemorrhage 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Flatulence 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Gastroesophageal reflux disease 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 3 0/7 (0%) 3 0/6 (0%) 3 0/11 (0%) 3
Gastrointestinal disorders - Other, specify 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 1/7 (14.3%) 3 0/8 (0%) 3 0/7 (0%) 3 0/6 (0%) 3 0/11 (0%) 3
Malabsorption 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Mucositis oral 1/6 (16.7%) 1 2/6 (33.3%) 3 1/6 (16.7%) 1 2/7 (28.6%) 2 0/8 (0%) 2 1/7 (14.3%) 1 2/6 (33.3%) 3 2/11 (18.2%) 2
Nausea 4/6 (66.7%) 5 3/6 (50%) 6 3/6 (50%) 5 5/7 (71.4%) 9 4/8 (50%) 8 4/7 (57.1%) 8 3/6 (50%) 6 4/11 (36.4%) 8
Oral hemorrhage 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 2
Oral pain 0/6 (0%) 0/6 (0%) 2/6 (33.3%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Rectal hemorrhage 0/6 (0%) 1/6 (16.7%) 2 0/6 (0%) 2 0/7 (0%) 2 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Stomach pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Vomiting 4/6 (66.7%) 5 2/6 (33.3%) 4 3/6 (50%) 4 5/7 (71.4%) 10 1/8 (12.5%) 4 4/7 (57.1%) 10 2/6 (33.3%) 4 2/11 (18.2%) 4
General disorders
Chills 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Disease Progression 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 2/11 (18.2%) 2
Edema limbs 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Fatigue 3/6 (50%) 4 5/6 (83.3%) 5 5/6 (83.3%) 7 3/7 (42.9%) 4 3/8 (37.5%) 3 2/7 (28.6%) 2 2/6 (33.3%) 2 6/11 (54.5%) 10
Fever 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Flu like symptoms 1/6 (16.7%) 2 0/6 (0%) 2 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
General disorders and administration site conditions - Other, specify 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Non-cardiac chest pain 2/6 (33.3%) 2 1/6 (16.7%) 1 0/6 (0%) 1 1/7 (14.3%) 1 2/8 (25%) 2 1/7 (14.3%) 1 1/6 (16.7%) 1 2/11 (18.2%) 2
Pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Hepatobiliary disorders
Hepatic pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Immune system disorders
Allergic reaction 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Infections and infestations
Infections and infestations - Other, specify 3/6 (50%) 3 0/6 (0%) 3 2/6 (33.3%) 3 1/7 (14.3%) 1 3/8 (37.5%) 4 1/7 (14.3%) 2 0/6 (0%) 2 2/11 (18.2%) 4
Lung infection 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Nail infection 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 2
Papulopustular rash 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Paronychia 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 2/11 (18.2%) 2
Skin infection 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 2/7 (28.6%) 3 0/8 (0%) 3 0/7 (0%) 3 0/6 (0%) 3 0/11 (0%) 3
Tooth infection 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Upper respiratory infection 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 2/6 (33.3%) 2 2/11 (18.2%) 2
Urinary tract infection 2/6 (33.3%) 2 0/6 (0%) 2 0/6 (0%) 2 1/7 (14.3%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 2/6 (33.3%) 3 0/11 (0%) 3
Vaginal infection 1/6 (16.7%) 1 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications - Other, specify 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Fall 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Investigations
Activated partial thromboplastin time prolonged 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 3 0/11 (0%) 3
Alanine aminotransferase increased 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 2/7 (28.6%) 2 4/6 (66.7%) 4 2/11 (18.2%) 2
Alkaline phosphatase increased 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Aspartate aminotransferase increased 1/6 (16.7%) 1 0/6 (0%) 1 2/6 (33.3%) 2 0/7 (0%) 2 2/8 (25%) 2 2/7 (28.6%) 2 4/6 (66.7%) 5 2/11 (18.2%) 2
Blood bilirubin increased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 2
Cardiac troponin I increased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Cholesterol high 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
CPK increased 0/6 (0%) 1/6 (16.7%) 1 2/6 (33.3%) 2 0/7 (0%) 2 2/8 (25%) 3 0/7 (0%) 3 3/6 (50%) 7 4/11 (36.4%) 6
Creatinine increased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 2 2/11 (18.2%) 2
Ejection fraction decreased 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Electrocardiogram QT corrected interval prolonged 2/6 (33.3%) 2 0/6 (0%) 2 0/6 (0%) 2 0/7 (0%) 2 3/8 (37.5%) 3 2/7 (28.6%) 2 4/6 (66.7%) 7 0/11 (0%) 7
Investigations - Other, specify 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Neutrophil count decreased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Platelet count decreased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 6 0/11 (0%) 6
Weight loss 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Metabolism and nutrition disorders
Anorexia 4/6 (66.7%) 4 1/6 (16.7%) 1 1/6 (16.7%) 1 1/7 (14.3%) 1 3/8 (37.5%) 3 3/7 (42.9%) 3 0/6 (0%) 3 0/11 (0%) 3
Hypercalcemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 0/7 (0%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Hyperkalemia 1/6 (16.7%) 1 1/6 (16.7%) 2 0/6 (0%) 2 3/7 (42.9%) 6 0/8 (0%) 6 1/7 (14.3%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Hypermagnesemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Hypertriglyceridemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Hypoalbuminemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 1/11 (9.1%) 2
Hypocalcemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Hypoglycemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Hypokalemia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Hypomagnesemia 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 2/8 (25%) 6 1/7 (14.3%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Hyponatremia 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Musculoskeletal and connective tissue disorders
Arthralgia 0/6 (0%) 2/6 (33.3%) 2 1/6 (16.7%) 1 0/7 (0%) 1 4/8 (50%) 7 1/7 (14.3%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Back pain 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 2/8 (25%) 5 2/7 (28.6%) 2 0/6 (0%) 2 1/11 (9.1%) 1
Bone pain 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Buttock pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Chest wall pain 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 0/11 (0%) 1
Muscle weakness lower limb 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Muscle weakness upper limb 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Musculoskeletal and connective tissue disorder - Other, specify 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Myalgia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Myositis 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Neck pain 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 1/8 (12.5%) 3 0/7 (0%) 3 0/6 (0%) 3 0/11 (0%) 3
Pain in extremity 0/6 (0%) 1/6 (16.7%) 2 0/6 (0%) 2 1/7 (14.3%) 1 1/8 (12.5%) 3 0/7 (0%) 3 1/6 (16.7%) 1 0/11 (0%) 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Nervous system disorders
Amnesia 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Cognitive disturbance 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Dizziness 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Dysgeusia 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 1/7 (14.3%) 1 0/8 (0%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Extrapyramidal disorder 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Headache 2/6 (33.3%) 4 1/6 (16.7%) 1 2/6 (33.3%) 2 1/7 (14.3%) 1 0/8 (0%) 1 1/7 (14.3%) 2 0/6 (0%) 2 1/11 (9.1%) 1
Lethargy 1/6 (16.7%) 1 0/6 (0%) 1 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Memory impairment 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Nervous system disorders - Other, specify 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Neuralgia 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Peripheral sensory neuropathy 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 1/6 (16.7%) 2 0/11 (0%) 2
Presyncope 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Somnolence 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Syncope 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Psychiatric disorders
Anxiety 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Confusion 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Depression 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Insomnia 1/6 (16.7%) 1 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 3/8 (37.5%) 4 0/7 (0%) 4 0/6 (0%) 4 0/11 (0%) 4
Libido increased 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Renal and urinary disorders
Cystitis noninfective 1/6 (16.7%) 2 0/6 (0%) 2 0/6 (0%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Urinary frequency 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Urinary incontinence 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 2/7 (28.6%) 2 0/6 (0%) 2 0/11 (0%) 2
Urinary urgency 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Reproductive system and breast disorders
Vaginal inflammation 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Pelvic pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Respiratory, thoracic and mediastinal disorders
Cough 2/6 (33.3%) 2 0/6 (0%) 2 2/6 (33.3%) 2 0/7 (0%) 2 2/8 (25%) 2 2/7 (28.6%) 2 1/6 (16.7%) 1 5/11 (45.5%) 6
Dyspnea 2/6 (33.3%) 2 2/6 (33.3%) 2 1/6 (16.7%) 1 1/7 (14.3%) 1 3/8 (37.5%) 3 1/7 (14.3%) 1 1/6 (16.7%) 1 2/11 (18.2%) 2
Epistaxis 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 0/7 (0%) 1 2/6 (33.3%) 2 1/11 (9.1%) 1
Hoarseness 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 2/6 (33.3%) 2 0/11 (0%) 2
Hypoxia 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Laryngospasm 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Nasal congestion 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Productive cough 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Respiratory, thoracic and mediastinal disorders - Other, specify 0/6 (0%) 1/6 (16.7%) 2 0/6 (0%) 2 0/7 (0%) 2 0/8 (0%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2
Sore throat 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Wheezing 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Skin and subcutaneous tissue disorders
Alopecia 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 1/7 (14.3%) 1 1/8 (12.5%) 1 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Dry skin 2/6 (33.3%) 2 1/6 (16.7%) 1 2/6 (33.3%) 3 2/7 (28.6%) 2 1/8 (12.5%) 1 0/7 (0%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Erythema multiforme 1/6 (16.7%) 1 0/6 (0%) 1 0/6 (0%) 1 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Hyperhidrosis 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 2 1/7 (14.3%) 1 0/6 (0%) 1 0/11 (0%) 1
Nail loss 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 0/6 (0%) 1/11 (9.1%) 1
Pain of skin 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 0/8 (0%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Palmar-plantar erythrodysesthesia syndrome 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Periorbital edema 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 0/11 (0%) 1
Photosensitivity 0/6 (0%) 1/6 (16.7%) 1 0/6 (0%) 1 0/7 (0%) 1 0/8 (0%) 1 1/7 (14.3%) 1 2/6 (33.3%) 2 0/11 (0%) 2
Pruritus 1/6 (16.7%) 1 1/6 (16.7%) 2 0/6 (0%) 2 3/7 (42.9%) 4 0/8 (0%) 4 0/7 (0%) 4 1/6 (16.7%) 1 1/11 (9.1%) 1
Purpura 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/7 (14.3%) 1 1/8 (12.5%) 2 0/7 (0%) 2 0/6 (0%) 2 1/11 (9.1%) 1
Rash acneiform 2/6 (33.3%) 2 3/6 (50%) 3 0/6 (0%) 3 1/7 (14.3%) 1 1/8 (12.5%) 1 3/7 (42.9%) 5 2/6 (33.3%) 3 1/11 (9.1%) 2
Rash maculo-papular 5/6 (83.3%) 7 3/6 (50%) 3 2/6 (33.3%) 4 4/7 (57.1%) 4 5/8 (62.5%) 7 3/7 (42.9%) 4 0/6 (0%) 4 7/11 (63.6%) 8
Skin and subcutaneous tissue disorders - Other, specify 1/6 (16.7%) 1 3/6 (50%) 5 2/6 (33.3%) 2 1/7 (14.3%) 1 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 1/11 (9.1%) 1
Skin ulceration 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 0/8 (0%) 0/7 (0%) 1/6 (16.7%) 1 1/11 (9.1%) 1
Vascular disorders
Flushing 0/6 (0%) 1/6 (16.7%) 1 1/6 (16.7%) 1 0/7 (0%) 1 0/8 (0%) 1 0/7 (0%) 1 1/6 (16.7%) 1 1/11 (9.1%) 1
Hot flashes 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 1/8 (12.5%) 1 0/7 (0%) 1 0/6 (0%) 1 0/11 (0%) 1
Hypertension 1/6 (16.7%) 2 2/6 (33.3%) 2 1/6 (16.7%) 1 1/7 (14.3%) 2 1/8 (12.5%) 1 3/7 (42.9%) 4 3/6 (50%) 4 5/11 (45.5%) 5
Thromboembolic event 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/7 (0%) 2/8 (25%) 2 0/7 (0%) 2 0/6 (0%) 2 0/11 (0%) 2

Limitations/Caveats

61 patients were enrolled. 3 withdrew before having vandetanib (Van) or selumetinib (Sel). 1 patient in Cohort 5b received Van but withdrew before having Sel and was excluded from the safety analysis. The remaining 57 patients had at least 1 dose of the combination and were included in the safety analysis population (46 in dose escalation, 11 in expansion). PFS was planned to be assessed at 12 weeks but was instead assessed at 10 and 18 weeks as disease assessments were performed every 2 cycles

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Regulatory Affairs Manager
Organization Cancer Research UK Centre for Drug Development
Phone +44 203 4696878
Email regulatory@cancer.org.uk
Responsible Party:
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01586624
Other Study ID Numbers:
  • CRUKD/11/001
  • 2011-000627-33
First Posted:
Apr 27, 2012
Last Update Posted:
Oct 7, 2021
Last Verified:
Sep 1, 2021